AMD Aging macula disorder age-related macular degeneration, all types
AREDS Age-related eye disease study AV Arteriovenous AVR Arteriovenous ratio BP Blood pressure CaV Cardiovascular CaVD Cardiovascular disease CDR Cup-to-disc ratio CeVD Cerebrovascular disease CI 95 % con fi dence interval CHD Coronary heart disease dAMD Dry late AMD similar as geographic
atrophy eAMD Early AMD GON Glaucomatous optic neuropathy GVFL Glaucomatous visual fi eld loss HR Hazard ratio HT Hypertensive
htOAG Hypertensive OAG IOP Intraocular pressure lAMD Late AMD includes dAMD and wAMD NT Normotensive ntOAG Normotensive OAG OAG Open-angle glaucoma OHT Ocular hypertension OR Odds ratio PeP Perfusion pressure POAG Primary open-angle glaucoma PSC Posterior subcapsular cataract PuP Pulse pressure RCT Randomized clinical trial RR Relative risk VCDR Vertical cup-to-disc ratio VF Visual fi eld VFL Visual fi eld loss wAMD Wet (neovascular) late AMD
4.1 Introduction
“Risk” factors as mentioned in the title should refer to factors that have been found to increase the probability of acquiring a disorder. Risk fac-tors do not automatically imply causality which can be demonstrated by aging: it is a risk factor for the three disorders in the title, but it is not the cause of these disorders. Causality can be assumed by the weight of evidence from a number of studies including strength, consistency, speci fi city, tem-porality, biologic gradient, plausibility, coherence, analogy, and experimental evidence (Hill 1965 ), but causality is never de fi nite. “Even the most
P. T. V. M. de Jong , MD, PhD, FARVO, FEBOphth, FRCOphth NIN , Meibergdreef 47 , 1105BA , Amsterdam , The Netherlands
AMC, Department of Ophthalmology , Meibergdreef 9 , 1105BA , Amsterdam , The Netherlands
LUMC, Department of Ophthalmology , Albinusdreef 2 , 2300RC Leiden , The Netherlands e-mail: [email protected]
Cataract, Age-Related Macular Degeneration, and Primary Open-Angle Glaucoma: Risk Factors
Paulus T. V. M. de Jong
34 P.T.V.M. de Jong
careful and detailed mechanistic dissection of indi-vidual events cannot provide more than associa-tions, albeit at a fi ner level” (Rothmann 1998 ). One epidemiological design to establish causality is a clinical trial in which we rely on randomization to balance treated or exposed groups and non-treated or non-exposed groups. A clinical trial, however, may have more problems obtaining well-balanced controls, and in case of diseased persons, its results are not necessarily applicable to the general popu-lation. In general, control persons in clinical trials will be healthier than the normal population and that also may make their results less generaliz-able to the target population. This holds also for case control studies that tend to compare the very ill with the very healthy ones. Prospective studies that follow groups with speci fi c risk factors for incidence of disease can also be powerful because of the temporality. However, population-based studies which follow groups over time may suffer from loss to follow-up or a lack of power when the disease of interest is relatively rare, but their advantage above clinic-based case–control studies is that the selection of controls from a population is often less biased. Also it should be kept in mind that access to clinical care may vary widely world-wide and that clinic-based study results may not be applicable to other populations. In one recent population-based study from the USA, for exam-ple, about 60 % of the participants had no health insurance (Choudhury et al. 2011 ) . Even within a Canadian clinic, poorer patients declined more expensive treatment (Chew et al. 2005 ) .
There are an increasing number of tools to test the validity of conclusions in medical articles. In treatment ef fi cacy and safety, one considers a meta-analysis of multiple, validly performed, ran-domized clinical trials (RCTs) as one of the highest levels of evidence, but these criteria are not always applicable to observational studies, as shown below. Risk factors are often derived from observa-tional studies, and the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) group made a checklist of 22 items used in case–control, cross- sectional, and cohort studies (Vandenbroucke et al. 2007 ) . Among these 22 items are, for example, prespeci fi ed hypothe-ses, key elements of study designs, sources of bias,
nonparticipation, and loss to follow-up. There is a wide range of risk factors for the disorders to be discussed in this chapter, but there is also a wide variation in the level of evidence for such factors. Without claiming completeness, Table 4.1 pro-vides the reader with an idea of the strength of evi-dence of risk factors.
Cataracts, primary open-angle glaucoma (POAG) and, less frequently, ageing macula dis-order (AMD) are categorized into primary and secondary forms. “Primary” often implies that we do not know the cause, and one could argue that once a cause is established, the disorder is not “primary” anymore. This is not absolute, because we know, for example, that aging or diabetes mellitus are associated with cataracts without knowing their exact pathophysiological mechanisms.
Around 1970, authors rightly decided to get rid of the term “senile” for aging cataract and macu-lar degeneration, but instead of “aging,” implying older age, they used the term “age-related” that can also be congenital or juvenile (Straub 1969 ; Sunness et al. 1985 ) . For that and other reasons (de Jong 2011 ) , I prefer “aging cataract” and “aging macula disorder” (AMD) over “senile” or “age-related cataract” and “age-related macular degen-eration,” the latter being one and the same as aging macula disorder and therefore has exactly the same acronym: AMD. Cataract and macula disor-der in the elderly would be better but would create completely new acronyms and I had to bow for the editors. The reader will see that all three disorders AMD, cataract, and POAG suffer from a lack of international classi fi cation or even standardization of de fi nitions, thus hampering comparisons.
4.2 Risk Factors for Cataract
Our classic handbooks on this subject (Duke-Elder 1964 ; Tasman and Jaeger 1999 ) list around 500 items in the section on cataracts describing nearly 75 different morphological types and around 200 different causes of cataracts. These were collected from publications by often astute and meticulous researchers, sometimes in extreme circumstances like world wars. Many of these past articles probably
would show defects according to the STROBE cri-teria and therefore should be classi fi ed as level III evidence, but that does not always deprive them of their value. For instance, how can we prove nowa-days with consent from the ethics committee that lightning or electrocution causes cataract (Duke-Elder 1964 )? These handbooks draw attention to differences in epidemiological and ophthalmo-logical thinking. It will be nearly impossible in a large population-based cohort study to exclude 200 different causes of cataract in each participant. Thus they might all be classi fi ed as aging cataracts, losing quite some speci fi c information on etiol-ogy. Another epidemiological hurdle is that there is essentially no universal de fi nition of cataract. Nearly every newborn baby has some lens opac-ity with an embryological, a fetal and, sometimes, the beginning of an infantile nucleus, and so has cataracts according to the Framingham Eye Study de fi nition: “A cataract is any opacity in the crys-talline lens of the eye” (Leibowitz et al. 1980 ) . Epidemiologically this may be correct, but pre-cisely at which point an opacity becomes a clinical cataract is uncertain. Even more so when cataract surgeons become more and more eager to fi nd indi-cations for surgery. Thus risk factors for cataract surgery as an endpoint of cataract seem tricky to
study (Chang et al. 2011 ) when these indications are not speci fi cally mentioned as is the case in most publications. Clinically, cataract may be de fi ned as a lens opacity or clouding that, after exclusion of other causes for visual loss, hampers the patient’s visual function in such a way that it hinders her or him from performing desired tasks. It may be clear that this is quite a subjective criterion. The patient should be the one, after hearing the pros and cons of surgery, to decide if the moment has come for an intervention. This clinical de fi nition, however, is hard to apply to the epidemiological search for risk factors. Thus the 75 morphological types of cataract are reduced to a small number, according to different grading systems (Leibowitz et al. 1980 ; Sparrow et al. 1986 ; West and Taylor 1986 ; Chylack et al. 1988 ; Hockwin 1994 ; Chew et al. 2010 ) . Frequently, this simpli fi cation leads to a division in nuclear, posterior subcortical (PSC), cortical, or mixed cataracts, with each two to fi ve grades per subdivision. It will be clear that this simpli fi cation, though necessary when comparing thousands of eyes, discards valuable information. These different grading systems in various studies are another source of confusion in assessing risk factors and might account for the often contradic-tory results.
Table 4.1 Quality of risk factor studies and according levels of evidence or conclusions
Based on Level of evidence
Systematic review/meta-analysis of at least two studies meeting criteria a to k I Prospective cohort study with I When based on several indepen-
dent studies with consistent results II When based on only one study
(a) Suf fi cient sample size (b) In a representative population (c) Clear de fi nition of inclusion/exclusion criteria or cases/controls (d) Clearly de fi ned primary outcomes (e) Clearly given comparison of baseline characteristics between groups (f) Adequate control for confounding (g) No selective follow-up (h) Suf fi cient follow-up time, related to natural history of disorder under study (i) Adequate accounting for loss to follow-up with numbers suf fi ciently
limited to have minimal potential for bias (j) Masked outcome assessment (k) Adequate statistics Study lacking two or more criteria a to k OR retrospective cohort study OR case–control study meeting criteria a to k, where appropriate
II When based on two studies III When based on one
Studies with no control group, OR case reports, OR expert opinions not clearly based on I or II
III
36 P.T.V.M. de Jong
As mentioned, cataracts will be divided into primary and secondary cataracts, the latter often clinically termed as “complicated cataract.” Once we fi nd a risk factor for cataract, for example, dia-betes mellitus or smoking, the exact cause of the cataract may still elude us, and so risk factors and causes may in this context be two different items.
Examples of the easier to de fi ne secondary cata-racts are cataracts due to chemical or physical trauma, multiorgan syndromes, in fl ammation, or metabolic disturbances (Table 4.2 ). However, the majority of those will not be discussed in detail in this chapter. This paragraph on risk factors will be con fi ned to primary cataract (of unknown origin) in persons or populations over the age of 40 years.
4.2.1 Risk Factors: Evidence Level I
4.2.1.1 Age We have known for millennia that age is a risk factor. Nevertheless, many papers still mention
this nowadays (Leibowitz et al. 1980 ; Hodge et al. 1995 ; Chang et al. 2011 ; Waudby et al. 2011 ) . The prevalence of cataract is 2.35 % between age 40 and 49 years and 74 % over age 80 (Congdon et al. 2004 ) in white populations. In India, the prevalence of any cataract rose from about 50 % below age 65 to 90 % above age 70 (Vashist et al. 2011 ) .
4.2.2 Risk Factors: Evidence Level II
4.2.2.1 Gender In seven studies including black, Hispanic, and white populations, the prevalence of cataracts in females varied between 53.3 and 61.1 % and in males between 38.9 and 46.7 % (Congdon et al. 2004 ) . Also in India and Asia, women had a higher prevalence (Vashist et al. 2011 ) . So, roughly estimated the prevalence of cataracts is 15 % higher in women than in men (West and Valmadrid 1995 ) .
Table 4.2 Examples of secondary or complicated cataract
Cause Examples Subgroups/examples
In fl ammation Uveitis Juvenile rheumatoid arthritis Bacterial/viral infection Herpes zoster Following angle-closure glaucoma “Glaukom fl ecken”
4.2.2.2 Geography Most studies agree that the prevalence of cat-aracts is higher in tropical areas with lower latitudes and in higher altitudes (Hollows and Moran 1981 ; Leske and Sperduto 1983 ; Brilliant et al. 1983 ; Javitt and Taylor 1994 ; Sasaki and Kojima 1994 ; West and Valmadrid 1995 ; Sapkota et al. 2010 ) . These differences, however, can also be due to genetics, hygiene, UV radiation at different latitudes, nutrition, toxic factors like cooking fuel, and many more factors. Around age 60, the prevalence of cata-ract in India is higher than in white populations, but around age 80 these prevalences are similar (Vashist et al. 2011 ) .
4.2.2.3 Light Exposure (Elevated) It is clear that there may be quite some over-lap between this risk factor and the geographi-cal one (see also remarks on light exposure in the AMD section). Nevertheless, in addition to the articles mentioned in the geography para-graph, there seems to be suf fi cient evidence to consider ultraviolet A and especially B as risk factors (Taylor et al. 1992 ; Hodge et al. 1995 ; Italian-American Cataract Study Group 1991 ; West et al. 1998 ) . Galactic cosmic space radia-tion could increase cortical cataracts (Chylack et al. 2009 ) . In Reykjavik, Scheimp fl ug images were taken, and light exposure was not a risk factor for nuclear cataracts (Arnarsson et al. 2002 ) .
4.2.2.4 Smoking Some early studies claiming smoking as a risk factor for cataract (Christen et al. 1992 ; Hankinson et al. 1992 ) were based on retrospec-tive self-reported data. There exist, however, cross-sectional or longitudinal studies that point to smoking as a risk factor for nuclear cataract (Flaye et al. 1989 ; West et al. 1989a ; Arnarsson et al. 2002 ; Tan et al. 2008b ) , all types of cata-ract (Krishnaiah et al. 2005b ; Wu et al. 2010 ) or cataract extraction (Krishnaiah et al. 2005b ; Lindblad et al. 2005 ) , encompassing various ethnic groups.
4.2.3 Risk Factors: Evidence Level III or Lower
4.2.3.1 Alcohol Intake (Elevated) Clinic-based case–control studies from the UK and the USA mentioned that heavy alcohol inges-tion was associated with cataracts, with a sugges-tion of a J-shaped curve, which means that moderate ingestion might be protective (West and Valmadrid 1995 ) . A population-based preva-lence study found similar associations (Ritter et al. 1993 ) especially for consumption of more than four alcohol units a day (Klein and Klein 2007 ) . Other studies could not corroborate this (Hodge et al. 1995 ; Wang et al. 2008 ) . Alcohol and smoking often went hand in hand, and one should keep in mind that both are based on his-tory data. The overall picture seems to be that alcohol has a minor in fl uence, if any, on cataract formation (Wang et al. 2008 ) .
4.2.3.2 Antioxidant Levels (Reduced), Nutrients, and Vitamin Supplements
There is disputed evidence as to whether nutri-ents play a role in the formation of aging cata-racts, and if so, which nutrients are the important ones. Often an association with only nuclear sclerosis or PSCs was found, and natural diet and supplements were intermingled in the analyses (Hodge et al. 1995 ) . Multivitamin supplements decreased the prevalence of nuclear cataracts (Sperduto et al. 1993 ; Chang et al. 2011 ) , and antioxidants seem to reduce the prevalence of cataract (West and Valmadrid 1995 ; Karppi et al. 2012 ) . In AREDS, it was found in a RCT that antioxidants (vitamins C and E, beta-car-otene) had no effects on risk or development of cataracts (Age-Related Eye Disease Study Research Group 2001 ) . In a very detailed review on nutrients and supplements, the evidence for protection against cataracts does not appear to be convincing (Chiu and Taylor 2007 ) , but in an Indian vitamin C-depleted population, there was an inverse association between vitamin C and cataract (Ravindran et al. 2011a ) . One should
38 P.T.V.M. de Jong
keep in mind that serum vitamin C levels are lower in Indian than in Western populations (Ravindran et al. 2011b ) .
4.2.3.3 Body Mass Index (BMI) (High) It is stated that both a low BMI (Athanasiov et al. 2008 ) especially in malnourished populations and a high BMI is associated with nuclear cataracts (Lim et al. 2009 ) in Asian populations. Another population-based longitudinal study found an increased risk of cortical cataracts and PSCs in persons with a high BMI (Younan et al. 2003 ) .
4.2.3.4 Cardiovascular Disease Cataracts were associated with systemic hyper-tension (Kahn et al. 1977 ) , but the subsequently reviewed literature was inconclusive (West and Valmadrid 1995 ) . A longitudinal study found that hypertensive patients had an odds ratio (OR) of 3.4 for PSCs and more cataract surgery was per-formed on participants with a history of angina (Younan et al. 2003 ) . Concerns might be raised that there could be confounding by indication through cataract-causing antihypertensive drugs. Also surgeons might be inclined to operate ear-lier on angina patients before the cardiac risk becomes too high for such a procedure.
4.2.3.5 Educational Status (Low) Higher education in general is associated with a higher socioeconomic status as well as a health-ier lifestyle with regard to food intake, smoking, and access to health services (Kahn et al. 1977 ; West and Valmadrid 1995 ; Chang et al. 2011 ) . Most studies fi nd that higher education is associ-ated with less cataract (Xu et al. 2010 ; Wu et al. 2010 ) .
4.2.3.6 Ethnicity Aborigines have more cataracts than non-Aborigines (Hollows and Moran 1981 ) . The population-based Barbados study showed a higher incidence of cataracts in blacks than whites (Leske et al. 2004 ) as did a clinic-based study with only 4 % black participants (Chang et al. 2011 ) . The same dif fi culties in ascertaining causality in the case of education, geography, light exposure, and nutri-tion may apply here (West et al. 1998 ) .
4.2.3.7 Genetics As is common nowadays, aging cataracts are considered to be a multifactorial disease. Contrary to congenital and familial or syndromal cataracts, hardly any of the genes are known. Two recent reviews highlight our present state of knowledge (San fi lippo et al. 2010 ; Shiels et al. 2010 ) . In a female twin study on nuclear cataracts, the vari-ance in expression was in 48 % determined by genetics, in 38 % by age, and in 14 % by environ-ment (Hammond et al. 2000 ) . The prevalence of cortical cataracts was similar for monozygotic and dizygotic twins, and although there were marked differences between clinical and digitized gradings, the genetic in fl uence was estimated to be 45 %, the environmental one 30 %, and that of age 14 % (Hammond et al. 2001 ) although twin studies might overestimate these risks.
4.2.3.8 Hormone Replacement Therapy (HRT)
The literature on HRT and cataracts is controver-sial. Cross-sectional studies suggested a protec-tive effect, but longitudinal studies did not (Klein et al. 2000 ; Freeman et al. 2004 ; Younan et al. 2003 ; Kanthan et al. 2010 ) . One study mentioned a higher risk for cataract surgery in women using HRT at any time (Lindblad et al. 2005 ) . A main concern for papers with cataract surgery as an outcome is the continuously changing indications for cataract surgery in high-volume cataract clin-ics. In underdeveloped countries, it may be the other way round – people who need surgery do not get it. Surgery in that situation might depend more on suf fi cient means for transport, care, and surgery fees.
4.2.3.9 Refraction For many years, it was the conventional wisdom of clinicians that myopic eyes develop nuclear cataracts at an earlier age than emmetropic or hyperopic eyes. This concept seems too simple. Most eyes undergo a hyperopic shift until the age of 65 or 70 years and after that a myopic shift. This holds true for different ethnicities (Lee et al. 1999 ; Guzowski et al. 2003 ; Wu et al. 2005 ; Fotedar et al. 2008 ) . The more nuclear cataract was present at baseline (around age 40
years), the higher the myopic shift after 5 years (Lee et al. 1999 ) .
4.3 Risk Factors for Aging Macula Disorder (AMD)
As with cataracts, there are different classi fi cation or grading systems for AMD. Most of them stick to an arbitrary age limit of 40 years or older for the patient or the participant in a study and the obligatory presence of drusen. Drusen are white, well-demarcated dots in the retina and may be small (<63 m m) to large ( ³ 125 m m) in size when seen with a certain standard magni fi cation on fundus color transparencies or digitized images. There is also a tendency to separate AMD into early AMD (eAMD) and late AMD (lAMD). Often eAMD is subdivided in two to three mutu-ally exclusive classes, characterized by increasing numbers and sizes of drusen and the presence of hyperpigmented or hypopigmented spots in the retina or its pigment epithelium (van Leeuwen 2003b ). Usually the person with eAMD has no or few visual complaints. Commonly, lAMD is subdivided in a dry form (dAMD), also called geographic atrophy, and a wet (wAMD) or neo-vascular form. dAMD is considered to be the result of dying retinal pigment epithelial cells with subsequent photoreceptor cell loss, lead-ing to gradual vision loss. On the other hand, wAMD originates from subretinal neovascular membranes with subsequent hemorrhages and scar tissue formation in the center of the retina; it can lead to visual loss in a few weeks or even overnight. In this chapter, the term AMD refers to all types of AMD.
At present, most epidemiological studies exclude certain retinal abnormalities to reach a diagnosis of AMD and do not use visual acuity in an eye as a diagnostic criterion for AMD. We have to keep in mind that AMD is always a diag-nosis by exclusion of others, and this may be another misclassi fi cation pitfall, especially in ret-rospective studies, because several different end-stage retinal disorders resemble each other. Table 4.3 provides the most common disorders that may mimic AMD.
4.3.1 Risk Factors: Evidence Level I
4.3.1.1 Aging By de fi nition, age is a risk factor for AMD. The estimated prevalence of drusen ³ 125 m m goes from 2.6 % at age 50 years to 27.5 % above age 80 years. For dAMD, this goes from 0.13 to 8 % and for wAMD from 0.18 to 9.5 %. For any lAMD, these fi gures rise from 0.27 to 13.6 % (Friedman et al. 2004a ) . A recent meta-analysis on 17,236 lAMD cases con fi rmed age as a risk factor in all studies (Chakravarthy et al. 2010 ) . The OR for AMD rose with 4.2 (95 % CI 3.8–4.6) per decade (Rudnicka et al. 2012 ) .
4.3.1.2 Cataract Surgery It remains questionable whether or not cataract surgery elevates the long-term risk of lAMD in patients with no AMD or only eAMD by what-ever mechanism, light exposure, or surgical trauma (van der Schaft et al. 1994 ). Thus perhaps this should be evidence level II. Two publications stated that there was no conclusive evidence and that a RCT was indicated (Smith et al. 2005 ; Patel 2007 ) . Because no such trials were performed, a recent Cochrane review concluded: “At this time, it is not possible to draw reliable conclusions from the available data to determine whether cat-aract surgery is bene fi cial or harmful in people with AMD” (Casparis et al. 2009 ) . Nevertheless, several prospective population-based studies found increased ORs up to 3.8 of late AMD after cataract surgery (Freeman et al. 2003 ; Krishnaiah et al. 2005a ; Cugati et al. 2006 ; Ho et al. 2008 ; Fraser-Bell et al. 2010 ; Choudhury et al. 2011 ) . A large meta-analysis of prospective cohort studies found that cataract surgery is a strong risk factor for wAMD (relative risk (RR) 3.05; 2.05–4.55) (Chakravarthy et al. 2010 ) .
4.3.1.3 Smoking Smoking is one of the best documented risk factors for AMD (Chakravarthy et al. 2010 ; Krishnaiah et al. 2005a ) since it was fi rst dem-onstrated in a clinic-based case–control study that smokers developed AMD on average 7 years earlier than nonsmokers (Paetkau et al. 1978 ) . Smoking as a risk factor was found in
40 P.T.V.M. de Jong
similar studies in white (Hyman et al. 1983 ) and Japanese persons (Tamakoshi et al. 1997 ) and also in twin studies (Seddon et al. 2006 ). Also in prevalence studies in Australia (McCarty et al. 2001 ) , China (Yang et al. 2011 ) , Europe (Vinding et al. 1992 ) , and India (Krishnaiah et al. 2005a ) and in Latinos (Fraser-Bell et al. 2008 ) and South Asians (Cackett et al. 2008 ) . Finally, it was best documented in population-based cohort studies in Australia (Mitchell et al. 2002b ) and Europe (van Leeuwen et al. 2003b ) and in white people (Klein et al. 2002 ) although only for eAMD, and Latinos (Choudhury et al. 2011 ) in the USA, as well as in pooled data from these studies (Tomany et al. 2004 ) .
4.3.2 Risk Factors: Evidence Level II
4.3.2.1 Body Mass Index (BMI) (Elevated) A recent review concluded that there is con-siderable evidence for an association between high BMI and AMD. The different associations with various types of AMD remain to be deter-mined (Cheung and Wong 2007 ) . Data from a RCT gave an OR 1.05 (95 % con fi dence interval (CI) 1.001–1.10) per 1 kg/m 2 rise in BMI (Klein et al. 2007a ) . There is hope for obese people. A decrease in waist-to-hip ratio of 3 % or more resulted, in a population-based cohort followed for 6 years, in lower odds for any AMD. Those losing 3 % waist-to-hip ratio had a 29 % drop in
Table 4.3 Examples of retinal disorders mimicking early or late AMD to be excluded before a de fi nition of AMD can be made
Mimicking Causes/examples Subgroups
Early AMD Asteroid hyalosis Circinate retinopathy Diabetic exudates Hypertension Kidney disorders Hyperpigmentations Medicine induced
odds, and the obese ones who were in the bottom decile of waist-to-hip ratio change dropped 59 %. Unfortunately, only 2 % of the obese reached this bottom decile (Peeters et al. 2008 ) .
4.3.2.2 Family History (Positive) Both in a clinic-based case–control study (Hyman et al. 1983 ) and a population-based cohort study (Klaver et al. 1998 ) , a positive family history is a risk factor for AMD. More details will be pro-vided in Chap. 5 .
4.3.2.3 w -3 Fatty Acids (Reduced) or Limited (Oily) Fish Ingestion
One of the fi rst studies mentioning an inverse association between fi sh intake and AMD was based on small numbers (0.6 % of the cohort) and retrospective AMD data with a visual cri-terion £ 20/30 within the de fi nition of AMD (Cho et al. 2001 ) . A prospective study saw a just signi fi cant reduction of lAMD with an OR 0.25 for those who consume fi sh at least three times a week (Chua et al. 2006 ) . After 10-year follow-up, the same group found that one fi sh serving per week reduced the risk of eAMD (RR 0.69) in people with below-median linoleic acid con-sumption (Tan et al. 2009 ) . One concern is that two or more fi sh servings failed to do so and that intake of nuts showed a similar pattern in that study. Furthermore, lAMD was not mentioned in the 10-year report. In a cross-sectional popula-tion-based study, eating oily fi sh at least once a week halved the risk of wAMD (Augood et al. 2008 ) . Similar protective effects were found in prospective population-based studies in combina-tion with some genotypes (Wang et al. 2009 ) and various other genetic variants (Ho et al. 2011 ) . A meta-analysis found a reduced risk of lAMD in high dietary intake of w -3 fatty acids or twice a week fi sh intake but concluded that there was insuf fi cient evidence to support these as factors in AMD prevention (Chong et al. 2008b ) .
4.3.2.4 Refraction: Hyperopia Since clinical case–control (Maltzman et al. 1979 ; Hyman et al. 1983 ) and most cross- sectional population-based studies (Kahn et al. 1977 ; Goldberg et al. 1988 ; Wang et al. 1998 ) linked
hyperopia with AMD, this was also con fi rmed for shorter axial length (Lavanya et al. 2010 ) . One population-based study could not con fi rm this (Klein et al. 1998 ) nor could its follow-up (Wong et al. 2002 ) . Another longitudinal popu-lation-based study could not con fi rm their cross-sectional fi nding that hyperopia was a risk factor for eAMD (Wang et al. 2004 ) . Yet another popu-lation-based study found that hyperopia was asso-ciated with both prevalent and incident AMD; the risk of AMD increased after 5 years per diopter of hyperopia by 5 % (Ikram et al. 2003 ) .
Obviously, there is a huge difference in cross-sectional and follow-up studies, and it is also clear that longitudinal studies do not always seem to provide the fi nal answer. On the one hand, the differences may be explained by power problems. On the other hand, naturally chang-ing refraction since baseline toward hyperopia below age 65 years and myopia above that age (Fotedar et al. 2008 ; Gudmundsdottir et al. 2005 ) may be a factor. It seems clear that there is an increasing risk of AMD with increasing hyperopia with crude RRs, going from 0.6 in myopia < −3.00 diopters (D) and 0.3 from −1.00 to −3.00 D, to 2.5 for hyperopia from +1.00 to +2.25 D, and 3.6 for hyperopia over +2.5 D (Wong et al. 2002 ) , although the RRs became nonsigni fi cant after adjusting for age. The difference between this latter study and the one by Ikram may be the statistical analysis: Wong used both eyes of a par-ticipant, while Ikram took the eye with the higher level of AMD or, when there was no difference, the right eye.
4.3.3 Risk Factors: Evidence Level III or Lower
4.3.3.1 Alcohol Intake (Elevated) The role of alcohol consumption in AMD is a matter of dispute. Prospective population-based studies found no risk (Boekhoorn et al. 2008 ) or even a slightly protective effect (Arnarsson et al. 2006 ) , while others found that over four con-sumptions a day increased the risk of dAMD (Knudtson et al. 2007 ) or only eAMD (Chong et al. 2008a ) . In addition, retrospective data from
a randomized trial found no marked risk (Ajani et al. 1999 ) so that, overall, it seems that alcohol is not a signi fi cant risk factor for AMD.
4.3.3.2 Arteriovenous (AV) Caliber of Retinal Vessels, Arteriovenous Ratio (AVR), Focal Narrowing, and AV Nicking
The AV caliber or their ratio was not associated with AMD (Ikram et al. 2005 ) , but AV nicking had an OR 2.6 (95 % CI 1.2–5.5) for late AMD (Liew et al. 2006 ) ; this could not be con fi rmed in another study (Cheung et al. 2011 ; van Leeuwen et al. 2003a ) . Finally, one cross-sectional study found an association between wider venular cali-ber and eAMD (Jeganathan et al. 2008 ) . For the time being, AV caliber or the AVR seem not to be major risk factors.
4.3.3.3 Cardiovascular (CaV-CaVD) and Cerebrovascular Disease (CeVD)
Like the Framingham Eye Study (Kahn et al. 1977 ) , a clinic-based case–control study found that hypertension is a risk factor for eAMD and wAMD as did a population-based cohort study (van Leeuwen et al. 2003a ) . Among Latinos, the link with wAMD held only for diastolic but not for systolic hypertension; high pulse pressure was a risk factor for AMD (van Leeuwen et al. 2003a ; Choudhury et al. 2011 ) , while low pulse pressure protected against wAMD (Fraser-Bell et al. 2008 ) . A clinic-based case–control study found that better CaV health was associated with prevalent AMD (McCarty et al. 2008 ) . Coronary heart disease (CHD) was associated with eAMD but not with lAMD (Sun 2012 ). Various measures of atherosclerosis were a risk for AMD (van Leeuwen et al. 2003a ) . In a meta-analysis, no prospective studies could fi nd hypertension, CaVD, or CeVD to be a risk fac-tor for AMD, but some case–control studies did (Chakravarthy et al. 2010 ) . Conversely, cases with AMD had no increased risk of CHD or CaVD (Fernandez et al. 2012 ) . One prospective population-based study differentiated CeVD and found that lAMD was a risk factor for any stroke and especially for cerebral hemorrhage
but not for cerebral infarction (Wieberdink et al. 2011 ) . All in all, CaVD nor CeVD seems to be a major risk factor.
A meta-analysis of fi ve prospective and six cross-sectional studies could not fi nd signi fi cant ORs or RRs for serum total or HDL cholesterol levels and AMD (Chakravarthy et al. 2010 ) .
4.3.3.5 Diabetes Mellitus Diabetes is also a dif fi cult risk factor to study because of the many different criteria for its diagnosis. These may vary from the many ways of obtaining historical data on the presence of diabetes to the use of oral treatment or injections and to measuring glucose levels in the blood. The latter may be performed randomly, after fasting overnight or even after a loading test. This hav-ing said, diabetes was not a risk factor for AMD in the pooled analysis of three large population-based incidence studies on mostly white partici-pants (Tomany et al. 2004 ) and in a subsequent analysis of dAMD (Klein et al. 2008 ) . A bor-derline signi fi cance was found in blacks (Leske et al. 2006 ) .
4.3.3.6 Ethnicity In a cross-sectional population-based study, eAMD and lAMD were more prevalent in whites than blacks (Friedman et al. 1999 ) like in another such study (Bressler et al. 2008 ) but for wAMD. Estimated prevalence of wAMD was 16 times and of dAMD 40 times higher in whites than in blacks (Friedman et al. 2004a ) . However, another population-based study in the USA using a non-mydriatic camera found a lower prevalence of eAMD in blacks but no major differences in prevalence of lAMD between Asians, blacks, Hispanics, or whites (Klein et al. 2006 ) . Only Native American ancestry seemed to predis-pose to dAMD (Fraser-Bell et al. 2005 ) . Another study on Hispanics in Arizona found a higher prevalence of eAMD but a lower of lAMD than in whites (Munoz et al. 2005 ) . The prevalences of eAMD seemed to be similar in Japan as in
a white Australian population, but lAMD was lower among Japanese women (Kawasaki et al. 2008 ) . The 9-year incidence of lAMD in Japan was lower than among whites and higher than in blacks (Yasuda et al. 2009 ) . The same prevalences were found in a white rural population as in an urban one in Italy (Piermarocchi et al. 2011 ) , and there was a similar prevalence in Spain (SEESG 2011 ). Rural Chinese had similar prevalences as whites for eAMD, but the prevalence was lower for lAMD (Yang et al. 2011 ) . There were no major differences in prevalence of lAMD between blacks, Chinese Asians, whites, and Hispanics (Chakravarthy et al. 2010 ) and Indian or Malay populations (Cheung et al. 2012 ).
4.3.3.7 Gender, Female Hormones, and Hormone Replacement Therapy (HRT)
Presumed lower prevalences of AMD in women led to hypotheses that more years of menstrua-tion, more children, or longer exposure to HRT might protect against AMD. Early menopause before age 45 years has a relative risk (RR) of 1.9 for lAMD (Vingerling et al. 1995 ) . HRT protected against wAMD in a clinic-based case–control study, and having one or more children was a risk factor (EDCCSG 1992 ). In a popu-lation-based 5-year incidence study, HRT had no effect (Klein et al. 2000 ) . A cross-sectional population-based study and in India found that older age at menarche elevated the risk of AMD (Nirmalan et al. 2004 ) . In this study, only 3 % of the women had AMD, and although the international classi fi cation was only intended for classi fi cation on fundus images (Bird et al. 1995 ) , the AMD diagnosis here was reached by ophthalmoscopy. In an RCT with estrogens or estrogens plus progestin on women aged 65 years and over, the AMD, prevalence was 21 %, but there were only 20 wAMD cases in the 2,635 taking also progestin. The conclusion was that estrogen plus progestin might protect against any soft drusen and wAMD (Haan et al. 2006 ) . Estrogens mediate their effects through intracel-lular receptors ESR1 and ESR2 . The ESR1 Pvu II- Xha I haplotype 1 had after a mean follow-up up of 7.7 years in heterozygous persons a 3.7 higher
risk of wAMD, and in homozygous persons, this was 4.7 (95 % CI 1.62–13.66) (Boekhoorn et al. 2007 ) . So HRT seems not to be a major protec-tive factor against AMD, and genetic combina-tions may evolve in due course, in combination with HRT, to carry a higher risk. A meta-analysis found no link between female gender and lAMD (Chakravarthy et al. 2010 ) , but there is some evi-dence that women have a slightly higher risk of wAMD (Rudnicka et al. 2012 ) .
4.3.3.8 Kidney Function (Reduced) There are some reports on links between reduced kidney function and eAMD or wAMD (Liew et al. 2008 ; Klein et al. 2009 ; Nitsch et al. 2009 ; Weiner et al. 2011 ; Choi et al. 2011 ) . They are partially contradictory. Some kidney diseases seem to be associated with white fl ecks in the retina (Duvall-Young et al. 1989 ) , and it remains questionable whether those fl ecks may be consid-ered to be drusen and have led to misclassi fi cation of eAMD (Table 4.3 ).
4.3.3.9 Light Exposure (Elevated) To con fi rm or deny the in fl uence of light expo-sure on AMD as in cataract is dif fi cult, if only because of the problems involved in obtaining reliable information on lifetime exposure, mea-suring its radiation levels, and changing views on retinal phototoxicity (Hunter et al. 2012 ) . There is no connection between UVB or blue light and AMD (West et al. 1989b ; Fletcher et al. 2008 ) , but the latter cross-sectional population-based study found signi fi cant links with wAMD in par-ticipants who also had the lowest quartile of anti-oxidant serum levels.
4.3.3.10 Medicines, Nutrients, and Supplements (Risk or Protective)
Medicines Associated with AMD Statins A cross-sectional study in participants from a hospital registry suggested a protective effect of statin use (Hall et al. 2001 ) . A cross-sectional population-based study found a low number (30) of lAMD cases. Angiotensin-converting enzyme inhibitors or ever having taken cholesterol- lowering
44 P.T.V.M. de Jong
medication elevated their risk of lAMD (McCarty et al. 2001 ) . In prospective studies, statin use either did not protect (van Leeuwen et al. 2001 ; Klein et al. 2007b ) or only protected against eAMD in one study with 7 % statin users and one case of lAMD (Tan et al. 2007 ) . Cochrane could not fi nd studies suitable for analysis of statins and AMD (Gehlbach et al. 2009 ) .
Aspirin In a cross-sectional population-based study, daily aspirin intake increased the risk of wAMD (de Jong et al. 2012 ) in contrast to earlier RCTs (Christen et al. 2001, 2009 ) . This is mentioned here only because of the widespread use of aspirin as primary and secondary prevention for CaVD and CeVD. In the pooled analysis of three population-based cohort studies, aspirin was not analyzed because less than 2 % of the baseline population mentioned aspirin use (Tomany et al. 2004 ) . However, one longitudinal population-based study found a HR 2.2 (CI 1.2–4.15) for nAMD in persons who regu-larly took aspirin for 10 years (Klein et al. 2012 ) and in another study with 15 years follow-up the OR for nAMD was 2.46 (1.25–4.83) (Liew et al. 2013 ). This warrants caution for aspirin as primary prevention of CaVD in persons with any AMD.
Antioxidant Intake (Low), Carotenoids as Lutein and Zeaxanthin Dietary studies often have a problem of recall bias when asking what food people were eating over a certain period in the past. That may be one reason for controversial outcomes. One pop-ulation-based cross-sectional study found that vitamin A but not vitamin C protected against AMD (Goldberg et al. 1988 ) , while a clinic-based case–control study found the opposite to be the case (Seddon et al. 1994 ) . The latter study mentioned the carotenoids lutein and zeaxanthin as being protective. A population-based cohort study mentioned modest protection by provi-tamin A and vitamin E for eAMD and by zinc against pigmentary abnormalities, but had power problems to look at lAMD (VandenLangenberg et al. 1998 ) . Later similar observational studies con fi rmed stronger protective effects of antioxi-dants on AMD (van Leeuwen et al. 2005 ; Tan et al. 2008a ) , but a review of six of these cohort
studies could not fi nd any signi fi cant effect (Ma et al. 2012 ) . A RCT found a protective effect of antioxidants plus zinc after excluding mild eAMD cases (Age-Related Eye Disease Study Research Group 2001 )
A Cochrane review examined three RCTs with alpha-tocopherol and beta-carotene supplements and concluded: “There was no evidence that anti-oxidant vitamin supplementation prevented or delayed the onset of AMD” (Evans and Henshaw 2009 ) . Another non-US review even mentioned a higher mortality risk in those taking supplements (Gerding and Thelen 2010 ) .
4.4 Risk Factors for Primary Open-Angle Glaucoma (POAG)
Glaucoma is a collective term for poorly under-stood disorders in retinal neurons. The neuronal cell death results in loss of retinal nerve fi bers. This nerve fi ber loss may become clinically man-ifest in red-free retinal images, nerve fi ber layer thinning, increased cupping of the optic nerve head leading to a larger (vertical) cup-to-disc ratio (VCDR), glaucomatous visual fi eld loss (GVFL) or a combination of these. However, this holds more for (primary) open-angle glaucoma ((P)OAG) than for (acute) angle-closure glau-coma, the latter being in some parts of the world more prevalent than POAG.
The classi fi cation of POAG seems to be an even greater problem than in AMD or cataract. In the same population-based data set, the prev-alence of POAG rose from 0.6 to 5.8 % (nearly ten times higher) in participants aged 80 years or over, simply by applying different diagnostic criteria from six more population-based stud-ies (Wolfs et al. 2000 ) ! The Framingham Eye Study had a two-step procedure with visual fi eld (VF) examination only in referred cases, before a diagnosis of POAG could be reached (Kahn et al. 1977 ) . Participants had OAG when one of fi ve GVFL criteria was present, “provided there was no de fi nite or doubtful diagnosis of acute, secondary, or other than open-angle glaucoma for the same eye.” When a person was not referred for de fi nite examination, OAG was negative. Wolfs only made a diagnosis of
de fi nite POAG based on the presence of glau-comatous optic neuropathy (GON) in combina-tion with GVFL that implies exclusion of other causes for VF loss, without intraocular pressure (IOP) as a diagnostic criterion. In this chapter, normotensive (NT) OAG (ntOAG) refers to an IOP that was found never to be over 21 mmHg in a diurnal curve; otherwise, the term ocular hypertension (OHT) is used. There are only a few population-based POAG incidence studies. Statistical power problems were encountered in these more often than in AMD because of the lower incidence of POAG.
As is the case with aging cataract, whenever we discover a cause for OAG, that part of OAG cannot be called primary anymore. Another simi-larity is that, clinically, we divide OAG into pri-mary and secondary. In Table 4.4 , some examples of secondary OAG are given. Risk factors of
POAG are provided in alphabetical order; its genetic background will be discussed in the next chapter.
4.4.1 Risk Factors: Evidence Level I
4.4.1.1 Age An extrapolation of data from eight population-based case–control and cohort studies estimated the prevalence of POAG in the USA in black women (men) between ages 40 and 49 years to be 1.51% (0.55)%. This was 0.34 (0.39)% for Hispanics and 0.83 (0.36)% for whites. Above the age of 80, these prevalences were 9.82 (13.21)% in blacks, 10.05 (7.91)% in Hispanics, and 6.94 (5.58)% in whites (Friedman et al. 2004b ) . This would point to a rise in prevalence of 6.5 times in elderly black women and to a prevalence of 29 times higher in old
Table 4.4 Examples of secondary open-angle glaucoma
In fl ammatory Uveitis Bacterial/viral infection Herpes zoster
Syphilis Metabolic disturbances Amyloidosis
Cystinosis Mucopolysaccharidosis
Multi organ/system syndromes Graves disease Lymphoma Phakomatosis
Neovascular glaucoma Diabetes mellitus Central retinal vein occlusion
Intraocular tumors Melanoma, metastasis Trauma Chemical Acid or lye burns Corticosteroids
Medicine use Physical Contusion of eye
Hyphema Irradiation Ionizing Perforation of eye Foreign body Surgery
Excluding congenital glaucoma (buphthalmos) and chronic angle-closure glaucoma
46 P.T.V.M. de Jong
Hispanic men. Smaller rises (2–3×) with aging were seen in China (Song et al. 2011 ) and India (4×) (Vijaya et al. 2008 ) . Age was a risk factor in all cohort studies (Mukesh et al. 2002 ; Leske et al. 2008 ; Czudowska et al. 2010 ; Cedrone et al. 2012 ) .
4.4.1.2 Ethnicity Blacks have a (4–5×) higher prevalence of POAG than whites both in a clinic-based screening pro-gram (Packer et al. 1959 ) and in a nonrepresenta-tive population screening (Frydman et al. 1966 ; Coulehan et al. 1980 ) . This held also for popu-lation-based prevalence studies (4–5×) (Tielsch et al. 1991 ; Rotchford et al. 2003 ) (2×) (Friedman et al. 2006 ) and cohort studies (3–6×) (Leske et al. 2007b ; Czudowska et al. 2010 ) . The prevalence in Hispanic persons lies between that of blacks and whites (Quigley et al. 2001 ) . Because of dif-ferences in POAG classi fi cation and pooling of various glaucoma types, it was hard to tell what the prevalences of POAG in Chinese (Song et al. 2011 ) , Indian (Vijaya et al. 2008 ) , or Bangladesh (Rahman et al. 2004 ) populations are. Two studies found a similar prevalence between Chinese and Europeans (He et al. 2006 ; Wang et al. 2010b ) .
4.4.1.3 Family History Despite concerns as to how reliable a family history may be (Mitchell et al. 2002a ) , most studies that looked into it found a positive family history to be a risk factor for POAG (Leske et al. 2008 ; Sun et al. 2012 ) . In one cohort study, family history only reached signi fi cance when IOP was left out of the analyses (Czudowska et al. 2010 ) . When looking at family databases (Wang et al. 2010a ) or actually examining family members (Wolfs et al. 1998 ; Hulsman et al. 2002 ) , the family history is a clear risk factor.
4.4.1.4 Glaucomatous Optic Neuropathy (GON) or Vertical Cup-to-Disc Ratio (VCDR)
The diagnosis GON is mostly made on the basis of arbitrary cutoff points of horizontal or vertical cup-to-disc ratios or local thinning (notching) of the rim of the cup (Wolfs et al. 2000 ) . Most pop-ulation-based incidence studies showed that a VCDR ³ 0.7 was a risk factor for POAG (Mukesh et al. 2002 ; Leske et al. 2007b ; Czudowska et al. 2010 ) , but one study failed to do so (Cedrone
et al. 2012 ) . One should take care in the study design not to confuse a diagnostic criterion for POAG with a risk factor for it.
4.4.1.5 Intraocular Pressure (IOP) That elevated IOP is associated with POAG is known for ages (Donders 1864 ; Packer et al. 1959 ; Armaly and Sayegh 1969 ) . The methodol-ogy for measuring the IOP as accurately as pos-sible has been extensively studied (Goldmann and Schmidt 1957 ; Armaly and Salamoun 1963 ; Perkins 1967 ; Dielemans et al. 1994 ) , but there is a still wide variation in applanation and inden-tation techniques. After a wide-ranging search through the literature and extensive testing, the most reliable measuring technique for IOP in epi-demiological studies seems to be the median of three applanation tonometry measurements under speci fi c conditions (Dielemans et al. 1994 ) . Even in experienced hands a fl uctuation of 2–3 mmHg can easily occur at a certain time point. In a cross-sectional clinic-based study, morning pressures were higher than later on the day as were IOPs in the pre-ovulation days in women (Bankes et al. 1968 ) . Despite the relative inac-curacy of IOP measurements, an elevated IOP is one of the strongest risk factors for POAG both in prevalence (Hollows and Graham 1966 ; Kahn et al. 1977 ; Bengtsson 1981 ; Sommer et al. 1991 ) and incidence studies (Mukesh et al. 2002 ; Leske et al. 2007b ; Czudowska et al. 2010 ; Cedrone et al. 2012 ) . The HR for incident GVFL per mm higher IOP at baseline was 1.11 (CI 1.06–1.15) (Czudowska et al. 2010 ) .
4.4.1.6 Refraction Myopia is a risk factor in most prevalence stud-ies, and the OR for POAG between −1.0 D and 3.0 D was 2.3 and ³ 3.0 D was 3.3 (Mitchell et al. 1999 ) (cf. the overview of 11 cross-sectional population-based studies in which the ORs below −3.0 D for POAG were 1.65 and ³ −3.0 D were 2.46) (Marcus et al. 2011 ) . There seems to be only one population-based incidence study with data on refraction that also found that myopia was a risk factor (Czudowska et al. 2010 ) . Longer axial length by itself was also a risk factor (Sia et al. 2010 ; Kuzin et al. 2010 ) as was a fl atter cor-nea in the latter study.
4.4.2.1 Disc Hemorrhages Disc hemorrhages come and go (Drance and Begg 1970 ) , and it was mentioned that one would need monthly examinations to catch them all (Drance 1989 ) . Despite the fact that they can easily be missed and that their origin is poorly understood, their signi fi cance as a risk factor for GVFL has been well documented for a long time in clinic-based (Drance and Begg 1970 ) and population-based studies (Ekstrom 1993 ) . A clinic-based study found a higher risk of GVFL associated with disc hemorrhages in NT than HT POAG (Rasker et al. 1997 ) . Hemorrhages, however, occur in about 1.4 % of the white population over 49 years old, and 70 % of these eyes had no POAG. Of the 108 POAG cases in a cross-sectional population-based study, 13.8 % had disc hemorrhages, and these were three times more prevalent in NT POAG (Healey et al. 1998 ) . This study found a low sensitivity of disc hemorrhages for POAG, about 13 %, and a high speci fi city of 99 %. In a clinical trial cohort, the HR for OAG progres-sion was 1.02 (CI 1.01–1.03) per percent higher frequency of visits in which disc hemorrhages were found (Leske et al. 2007a ) .
4.4.3 Risk Factors: Evidence Level III or Lower
4.4.3.1 Alcohol Alcohol intake seems hardly a risk factor for POAG, unless huge amounts of beer are consumed daily, simulating the old water-loading test from the 1960s (Xu et al. 2009 ; Ramdas et al. 2011a ) .
4.4.3.2 Blood (BP) (Elevated) and Perfusion Pressure (PeP) (Lowered)
The association between elevated systolic and diastolic blood pressure (BP) and glaucoma was noted over 100 years ago. It seems that various forms of glaucoma were pooled in that clinical study (Kuemmell 1911 ) . Associations between elevated BP and elevated IOP later became known (Leighton and Phillips 1972 ; Kahn et al.
1977 ) and were con fi rmed in many population-based cohort studies (Klein et al. 2005 ) . Systemic hypertension was associated with POAG in pop-ulation-based cross-sectional studies (Dielemans et al. 1995 ; Bonomi et al. 2000 ; Mitchell et al. 2004 ) . Because of power problems, systemic hypertension was not con fi rmed as a risk factor in the follow-up to one of these (Hulsman et al. 2007 ) . Elevated PeP (2/3 mean arterial BP–IOP) was a risk factor for high tension (HT) OAG but not for NT OAG. A low diastolic PeP was a risk for both NT and HT OAG (Hulsman et al. 2007 ) . Recently, it was concluded from a population-based cohort study that the ocular PeP is a risk factor for POAG but mainly because IOP (another important risk factor) is also incorporated into the PeP (Ramdas et al. 2011b ) . Overall systemic hypertension seems to be an inconsistent risk fac-tor for OAG, but diastolic hypotension might be a factor (Leske et al. 2007b, 2008 ; Leske 2009 ) .
4.4.3.3 Central Corneal Thickness (CCT) That corneal parameters could in fl uence the exact measurement of the IOP has been known for about 150 years (Donders 1863 ; Goldmann and Schmidt 1957 ) . The CCT can be measured with an optical tachymeter or an ultrasonic device, the former giving on average 4 m m (Doughty and Zaman 2000 ) lower values. The CCT was independent of sex and age in a cross-sectional population-based study and was 16 m m thicker in ocular hypertension and 21.5 m m thinner in POAG cases (Wolfs et al. 1997 ) . Another simi-lar study, in Mongolia, found a 5 m m decrease per decade of aging in men and 6 m m in women; a 10 m m increase in CCT was associated with a 0.21 mmHg increase in IOP (Foster et al. 1998 ) . Age seems not to play a role on CCT in whites but does so in nonwhites (Doughty and Zaman 2000 ) and was on average 17 m m lower in African-Americans (Shimmyo et al. 2003 ) . In the UK, no relation between CCT and age was found (Foster et al. 2011 ) . The CCT was not associated with POAG in 938 population-derived participants but was so in 243 hospital-derived POAG cases, possibly due to the low number of POAG cases in the community (Day et al. 2011 ) . A Japanese population-based prevalence study found no link between CCT and POAG (Iwase et al. 2004 ) nor
48 P.T.V.M. de Jong
did a Malay (Perera et al. 2010 ) or a Chinese one (Wang et al. 2011 ) . A thinner CCT was a risk factor in a population-based cohort study (Leske et al. 2008 ) . The CCT increases at higher altitude (Morris et al. 2007 ) . Care should be taken when considering lower CCT as a risk factor for POAG, given the complexity of CCT variables which are in fl uenced by changes caused by age, eye or col-lagen disorders, IOP, and altitude.
4.4.3.4 Diabetes Mellitus Diabetes is often mentioned as a risk factor for POAG. Diabetes may create secondary OAG due to neovascular glaucoma, glaucoma after a com-plicated cataract extraction or after infection; those are considered to be secondary OAG. Diabetes was not a risk factor for POAG in two cross-sectional population-based studies (Tielsch et al. 1995 ; Tarkkanen et al. 2008 ) nor in such an incidence study (de Voogd et al. 2006 ) .
4.4.3.5 Education One population-based prevalence study from Singapore mentioned that persons with lower education and income had a higher mean IOP (Yip et al. 2007 ) , but this could not be con fi rmed either in a cohort study of blacks (Leske et al. 2008 ) or one of whites (Ramdas et al. 2011a ) .
4.4.3.6 Glaucomatous Visual Field Loss (GVFL)
Glaucomatous visual fi eld loss should be consid-ered more as sign of de fi nite POAG than a risk factor. The prevalence of any VFL in the general population was 3 % between the ages of 55–64 and 17 % over age 85. POAG was the leading cause in 27 % of the eyes (Ramrattan et al. 2001 ) as it was in 24 % of eyes with incident VFL (Skenduli-Bala et al. 2005 ) .
4.4.3.7 Sex, Early Menopause, and Hormone Replacement Therapy (HRT)
Sex as a risk factor is controversial from the fi rst documented higher prevalence in women in a clinic-based study (Haffmans 1861 ). Menopause before age 45 was associated with OAG (Hulsman et al. 2001 ) , and haplotype 1 of the estrogen receptor beta was a risk factor for POAG in men
(de Voogd et al. 2008 ) and for a high IOP in clinic-derived Japanese women (Mabuchi et al. 2010 ) , although they seemed not to check the time of measuring the IOP during the menstrual cycle (Bankes et al. 1968 ) . One population-based white Australian cohort study found a nonsigni fi cant higher incidence of POAG in men (Mukesh et al. 2002 ) as did a study in Italy (Cedrone et al. 2012 ) ; two Swedish studies mentioned a twice higher incidence in women (Bengtsson 1989 ; Ekström 2008 ) , while large cohort studies found a higher risk in black (Leske et al. 2007b ) and white men (Czudowska et al. 2010 ) . Given this controver-sial data across various ethnicities, sex does not appear to be a de fi nite universal risk factor.
4.4.3.8 Smoking Hardly any incidence studies looked at smok-ing. There was a slightly positive association between smoking and IOP (Lee et al. 2003 ) , but smoking was not a risk factor in a large population-based cohort study (Ramdas et al. 2011a ) .
4.4.3.9 Vascular There is extensive literature on vascular risk fac-tors for POAG (Grieshaber et al. 2007 ) or autono-mous dysregulation, but, in my view, most of this depends on circumstantial evidence. As may be clear from my comments on BP, PeP, and diabe-tes, there is still much uncertain or controversial in the vascular origin of POAG. The reader is referred to a wide-ranging review of this matter (Yanagi et al. 2011 ) .
Acknowledgments Con fl ict of interest: none; Ethical standards: Informed consent – not applicable; Animal rights – not applicable.
References
Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol 119(10):1439–1452
Ajani UA et al (1999) A prospective study of alcohol con-sumption and the risk of age-related macular degen-eration. Ann Epidemiol 9(3):172–177
Armaly MF, Sayegh RE (1969) The cup-disc ratio. The fi ndings of tonometry and tonography in the normal eye. Arch Ophthalmol 82(2):191–196
Arnarsson A et al (2002) Risk factors for nuclear lens opaci fi cation: the Reykjavik Eye Study. Dev Ophthalmol 35:12–20
Arnarsson A et al (2006) Risk factors for fi ve-year inci-dent age-related macular degeneration: the Reykjavik Eye Study. Am J Ophthalmol 142(3):419–428
Athanasiov PA et al (2008) Cataract in rural Myanmar: prevalence and risk factors from the Meiktila Eye Study. Br J Ophthalmol 92(9):1169–1174
Augood C et al (2008) Oily fi sh consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 88(2):398–406
Bankes JL et al (1968) Bedford glaucoma survey. Br Med J 1(5595):791–796
Bengtsson B (1981) The prevalence of glaucoma. Br J Ophthalmol 65(1):46–49
Bengtsson BO (1989) Incidence of manifest glaucoma. Br J Ophthalmol 73(7):483–487
Bird AC et al (1995) An international classi fi cation and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 39(5):367–374
Boekhoorn SS et al (2007) Estrogen receptor alpha gene polymorphisms associated with incident aging macula disorder. Invest Ophthalmol Vis Sci 48(3):1012–1017
Boekhoorn SS et al (2008) Alcohol consumption and risk of aging macula disorder in a general population: the Rotterdam Study. Arch Ophthalmol 126(6):834–839
Bonomi L et al (2000) Vascular risk factors for primary open angle glaucoma: the Egna-Neumarkt Study. Ophthalmology 107(7):1287–1293
Bressler SB et al (2008) Racial differences in the preva-lence of age-related macular degeneration: the Salisbury Eye Evaluation (SEE) Project. Arch Ophthalmol 126(2):241–245
Brilliant LB et al (1983) Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas. Am J Epidemiol 118(2):250–264
Cackett P et al (2008) Smoking, cardiovascular risk fac-tors, and age-related macular degeneration in Asians: the Singapore Malay Eye Study. Am J Ophthalmol 146(6):960–967
Casparis H, Lindsley K, Bressler NB (2009) Surgery for cataracts in people with age-related macular degenera-tion. Cochrane Database Syst Rev (1):CD006757
Cedrone C et al (2012) The 12-year incidence of glau-coma and glaucoma-related visual fi eld loss in Italy: the Ponza eye study. J Glaucoma 21(1):1–6
Chakravarthy U et al (2010) Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 10:31
Chang JR et al (2011) Risk factors associated with inci-dent cataracts and cataract surgery in the Age-related
Eye Disease Study (AREDS): AREDS report number 32. Ophthalmology 118(11):2113–2119
Cheung N, Wong TY (2007) Obesity and eye diseases. Surv Ophthalmol 52(2):180–195
Cheung CM et al (2011) Retinal arteriolar wall signs and early age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol 152(1):108–113
Cheung CMG, Tai ES, Kawasaki R et al (2012) Prevalence of and risk factors for age-related macular degenera-tion in a multiethnic Asian cohort. Arch Ophthalmol 130(4):480–486
Chew H et al (2005) Socioeconomic status and clinical features of patients undergoing photodynamic therapy or transpupillary thermotherapy for subfoveal choroi-dal neovascularization due to age-related macular degeneration. Can J Ophthalmol 40(3):384–388
Chew EY et al (2010) Evaluation of the age-related eye disease study clinical lens grading system AREDS report no. 31. Ophthalmology 117(11):2112–2119
Chiu CJ, Taylor A (2007) Nutritional antioxidants and age-related cataract and maculopathy. Exp Eye Res 84(2):229–245
Cho E et al (2001) Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 73(2):209–218
Chong EW et al (2008a) Alcohol consumption and the risk of age-related macular degeneration: a systematic review and meta-analysis. Am J Ophthalmol 145(4):707–715
Chong EW et al (2008b) Dietary omega-3 fatty acid and fi sh intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol 126(6):826–833
Choudhury F et al (2011) Risk factors for four-year inci-dence and progression of age-related macular degen-eration: the los angeles latino eye study. Am J Ophthalmol 152(3):385–395
Christen WG et al (1992) A prospective study of cigarette smoking and risk of cataract in men. JAMA 268(8):989–993
Christen WG et al (2001) Age-related maculopathy in a randomized trial of low-dose aspirin among US physi-cians. Arch Ophthalmol 119(8):1143–1149
Christen WG et al (2009) Low-dose aspirin and medi-cal record-con fi rmed age-related macular degenera-tion in a randomized trial of women. Ophthalmology 116(12):2386–2392
Chua B et al (2006) Dietary fatty acids and the 5-year inci-dence of age-related maculopathy. Arch Ophthalmol 124(7):981–986
Chylack LT Jr et al (1988) Lens opacities classi fi cation system. Arch Ophthalmol 106(3):330–334
Chylack LT Jr et al (2009) NASA study of cataract in astronauts (NASCA). Report 1: cross-sectional study of the relationship of exposure to space radiation and risk of lens opacity. Radiat Res 172(1):10–20
50 P.T.V.M. de Jong
Congdon N et al (2004) Prevalence of cataract and pseu-dophakia/aphakia among adults in the United States. Arch Ophthalmol 122(4):487–494
Coulehan JL et al (1980) Racial differences in intraocu-lar tension and glaucoma surgery. Am J Epidemiol 111(6):759–768
Cugati S et al (2006) Cataract surgery and the 10-year inci-dence of age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology 113(11):2020–2025
Czudowska MA et al (2010) Incidence of glaucomatous visual fi eld loss: a ten-year follow-up from the Rotterdam Study. Ophthalmology 117(9):1705–1712
Day AC et al (2011) Central corneal thickness and glau-coma in East Asian people. Invest Ophthalmol Vis Sci 52(11):8407–8412
de Jong PT (2011) Re fl ections on “hot” blind spots: les-sons from research on aging macula disorder and glau-coma: the Weisenfeld lecture. Invest Ophthalmol Vis Sci 52(10):7717–7724, 7716
de Jong PT et al (2012) Associations between aspirin use and aging macula disorder: the European Eye Study. Ophthalmology 119(1):112–118
de Voogd S et al (2006) Is diabetes mellitus a risk factor for open-angle glaucoma? The Rotterdam Study. Ophthalmology 113(10):1827–1831
de Voogd S et al (2008) Estrogen receptors alpha and beta and the risk of open-angle glaucoma: the Rotterdam Study. Arch Ophthalmol 126(1):110–114
Dielemans I et al (1994) Reliability of intraocular pres-sure measurement with the Goldmann applanation tonometer in epidemiological studies. Graefes Arch Clin Exp Ophthalmol 232(3):141–144
Dielemans I et al (1995) Primary open-angle glaucoma, intraocular pressure, and systemic blood pressure in the general elderly population. The Rotterdam Study. Ophthalmology 102(1):54–60
Donders FC (1863) Vorzeigung neuer, ophthalmometrischer Instrumente; (Ophthalmo) tonometer. (Demonstration of new ophthalmometric instruments: (Ophthalmo) tonometer). Klin Monbl Augenheilkd 1:1502–1504
Donders FC (1864) Ueber Glaucom (On glaucoma). Klin Monbl Augenheilkd 2:433–437
Doughty MJ, Zaman ML (2000) Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol 44(5):367–408
Drance SM (1989) Disc hemorrhages in the glaucomas. Surv Ophthalmol 33(5):331–337
Drance SM, Begg IS (1970) Sector haemorrhage – a prob-able acute ischaemic disc change in chronic simple glaucoma. Can J Ophthalmol 5(2):137–141
Duke-Elder S (1964) System of ophthalmology, vol III, Normal and abnormal development, part 2, congenital deformities. Henry Kimpton, London
Ekstrom C (1993) Elevated intraocular pressure and pseu-doexfoliation of the lens capsule as risk factors for
chronic open-angle glaucoma. A population-based fi ve-year follow-up study. Acta Ophthalmol (Copenh) 71(2):189–195
Ekström C (2008) Incidence of open-angle glaucoma in central Sweden. Acta Ophthalmol 86(7):747–754
Evans J, Henshaw K (2009) Antioxidant vitamin and min-eral supplements for preventing age-related macular degeneration (review). Cochrane Database Syst Rev (1):CD000253
Fernandez AB et al (2012) Age-related macular degenera-tion and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. Ophthalmology 119:765–770
Flaye DE et al (1989) Cataracts and cigarette smoking. The City Eye Study. Eye (Lond) 3(Pt 4):379–384
Fletcher AE et al (2008) Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol 126(10):1396–1403
Foster PJ et al (1998) Central corneal thickness and intraocular pressure in a Mongolian population. Ophthalmology 105(6):969–973
Foster PJ et al (2011) Intraocular pressure and corneal biomechanics in an adult British population: the EPIC-Norfolk eye study. Invest Ophthalmol Vis Sci 52(11):8179–8185
Fotedar R et al (2008) Relationship of 10-year change in refraction to nuclear cataract and axial length fi ndings from an older population. Ophthalmology 115(8):1273–1278, 1278
Fraser-Bell S et al (2005) Sociodemographic factors and age-related macular degeneration in Latinos: the Los Angeles Latino Eye Study. Am J Ophthalmol 139(1):30–38
Fraser-Bell S et al (2008) Cardiovascular risk factors and age-related macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol 145(2):308–316
Fraser-Bell S et al (2010) Ocular risk factors for age-related macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol 149(5):735–740
Freeman EE et al (2003) Is there an association between cataract surgery and age-related macular degenera-tion? Data from three population-based studies. Am J Ophthalmol 135(6):849–856
Freeman EE et al (2004) Incidence and progression of lens opacities: effect of hormone replacement therapy and reproductive factors. Epidemiology 15(4):451–457
Friedman DS et al (1999) Racial differences in the preva-lence of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology 106(6):1049–1055
Friedman DS et al (2004a) Prevalence of age-related mac-ular degeneration in the United States. Arch Ophthalmol 122(4):564–572
Friedman DS et al (2004b) Prevalence of open-angle glau-coma among adults in the United States. Arch Ophthalmol 122(4):532–538
Friedman DS et al (2006) The prevalence of open-angle glaucoma among blacks and whites 73 years and older: the Salisbury Eye Evaluation Glaucoma Study. Arch Ophthalmol 124(11):1625–1630
Frydman JE et al (1966) Glaucoma detection in Florida. JAMA 198(12):1237–1240
Gehlbach P, Li T, Hatef E (2009) Statins for age-related macular degeneration. Cochrane Database Syst Rev (3):CD006927
Gerding H, Thelen U (2010) Primary and secondary pro-phylaxis of AMD by antioxidants: current risk-bene fi t data. Klin Monbl Augenheilkd 227(4):298–301
Goldberg J et al (1988) Factors associated with age-related macular degeneration. An analysis of data from the fi rst National Health and Nutrition Examination Survey. Am J Epidemiol 128(4):700–710
Goldmann H, Schmidt T (1957) Ueber Applanation-stonometrie. Ophthalmologica 134:221–242
Grieshaber MC, Mozaffarieh M, Flammer J (2007) What is the link between vascular dysregulation and glau-coma? Surv Ophthalmol 52(Suppl 2):S144–S154
Gudmundsdottir E, Arnarsson A, Jonasson F (2005) Five-year refractive changes in an adult population: Reykjavik Eye Study. Ophthalmology 112(4):672–677
Guzowski M et al (2003) Five-year refractive changes in an older population: the Blue Mountains Eye Study. Ophthalmology 110(7):1364–1370
Haan MN et al (2006) Hormone therapy and age-related macular degeneration: the Women’s Health Initiative Sight Exam Study. Arch Ophthalmol 124(7):988–992
Haffmans JHA (1861) Beiträge zur Kenntniss des Glaucoms. Archiv für Ophthalmologie 8:124–178
Hall NF et al (2001) Risk of macular degeneration in users of statins: cross sectional study. BMJ 323(7309):375–376
Hammond CJ et al (2000) Genetic and environmental fac-tors in age-related nuclear cataracts in monozygotic and dizygotic twins. N Engl J Med 342(24):1786–1790
Hammond CJ et al (2001) The heritability of age-related cortical cataract: the twin eye study. Invest Ophthalmol Vis Sci 42(3):601–605
Hankinson SE et al (1992) A prospective study of ciga-rette smoking and risk of cataract surgery in women. JAMA 268(8):994–998
He M et al (2006) Prevalence and clinical characteristics of glaucoma in adult Chinese: a population-based study in Liwan District, Guangzhou. Invest Ophthalmol Vis Sci 47(7):2782–2788
Healey PR et al (1998) Optic disc hemorrhages in a popu-lation with and without signs of glaucoma. Ophthalmology 105(2):216–223
Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58(5):295–300
Ho L et al (2008) Cataract surgery and the risk of aging macula disorder: the Rotterdam study. Invest Ophthalmol Vis Sci 49(11):4795–4800
Ho L et al (2011) Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and omega-3 fatty acids: the Rotterdam study. Arch Ophthalmol 129(6):758–766
Hockwin O (1994) Cataract classi fi cation. Doc Ophthalmol 88(3–4):263–275
Hodge WG, Whitcher JP, Satariano W (1995) Risk factors for age-related cataracts. Epidemiol Rev 17(2):336–346
Hollows FC, Graham PA (1966) Intra-ocular pressure, glaucoma, and glaucoma suspects in a de fi ned popula-tion. Br J Ophthalmol 50(10):570–586
Hollows F, Moran D (1981) Cataract – the ultraviolet risk factor. Lancet 2(8258):1249–1250
Hulsman CA et al (2001) Is open-angle glaucoma associ-ated with early menopause? The Rotterdam Study. Am J Epidemiol 154(2):138–144
Hulsman CA et al (2002) Family score as an indicator of genetic risk of primary open-angle glaucoma. Arch Ophthalmol 120(12):1726–1731
Hulsman CA et al (2007) Blood pressure, arterial stiff-ness, and open-angle glaucoma: the Rotterdam study. Arch Ophthalmol 125(6):805–812
Hunter JJ et al (2012) The susceptibility of the retina to photochemical damage from visible light. Prog Retin Eye Res 31(1):28–42
Hyman LG et al (1983) Senile macular degeneration: a case–control study. Am J Epidemiol 118(2):213–227
Ikram MK et al (2003) Relationship between refraction and prevalent as well as incident age-related macul-opathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 44(9):3778–3782
Ikram MK et al (2005) Retinal vessel diameters and the risk of incident age-related macular disease: the Rotterdam Study. Ophthalmology 112(4):548–552
Iwase A et al (2004) The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 111(9):1641–1648
Javitt JC, Taylor HR (1994) Cataract and latitude. Doc Ophthalmol 88(3–4):307–325
Jeganathan VS et al (2008) Retinal vascular caliber and age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol 146(6):954–959
Kahn HA et al (1977) The Framingham Eye Study. II. Association of ophthalmic pathology with single vari-ables previously measured in the Framingham Heart Study. Am J Epidemiol 106(1):33–41
Kanthan GL et al (2010) Exogenous oestrogen exposure, female reproductive factors and the long-term inci-dence of cataract: the Blue Mountains Eye Study. Acta Ophthalmol 88(7):773–778
Karppi J, Laukkanen JA, Kurl S (2012) Plasma lutein and zeaxanthin and the risk of age-related nuclear cataract among the elderly Finnish population. Br J Nutr 108:148–154
Kawasaki R et al (2008) Prevalence and risk factors for age-related macular degeneration in an adult Japanese population: the Funagata study. Ophthalmology 115(8):1376–1381, 1381
Klaver CC et al (1998) Genetic risk of age-related macul-opathy. Population-based familial aggregation study. Arch Ophthalmol 116(12):1646–1651
Klein R et al (1998) The relationship of ocular factors to the incidence and progression of age-related macul-opathy. Arch Ophthalmol 116(4):506–513
Klein BE, Klein R, Lee KE (2000) Reproductive expo-sures, incident age-related cataracts, and age-related
52 P.T.V.M. de Jong
maculopathy in women: the Beaver Dam Eye Study. Am J Ophthalmol 130(3):322–326
Klein R et al (2002) Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 156(7):589–598
Klein BE, Klein R, Knudtson MD (2005) Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study. Br J Ophthalmol 89(3):284–287
Klein R et al (2006) Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis. Ophthalmology 113(3):373–380
Klein BE, Klein R (2007) Lifestyle exposures and eye dis-eases in adults. Am J Ophthalmol 144(6):961–969
Klein R et al (2007a) Cardiovascular disease, its risk fac-tors and treatment, and age-related macular degenera-tion: Women’s Health Initiative Sight Exam ancillary study. Am J Ophthalmol 143(3):473–483
Klein R, Knudtson MD, Klein BE (2007b) Statin use and the fi ve-year incidence and progression of age-related macular degeneration. Am J Ophthalmol 144(1):1–6
Klein R et al (2008) The epidemiology of progression of pure geographic atrophy: the Beaver Dam Eye Study. Am J Ophthalmol 146(5):692–699
Klein R et al (2009) Serum cystatin C level, kidney dis-ease markers, and incidence of age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 127(2):193–199
Klein BEK, Kerri PH, Gangnon RE, Dreyer JO, Lee KE, Klein R (2012) Long-term use of aspirin and age-related macular degeneration. JAMA 308(23):2469–2478
Knudtson MD, Klein R, Klein BE (2007) Alcohol con-sumption and the 15-year cumulative incidence of age-related macular degeneration. Am J Ophthalmol 143(6):1026–1029
Krishnaiah S et al (2005a) Risk factors for age-related macular degeneration: fi ndings from the Andhra Pradesh eye disease study in South India. Invest Ophthalmol Vis Sci 46(12):4442–4449
Krishnaiah S et al (2005b) Smoking and its association with cataract: results of the Andhra Pradesh eye dis-ease study from India. Invest Ophthalmol Vis Sci 46(1):58–65
Kuemmell R (1911) Untersuchungen ueber Glaukom und Blutdruck (Investigations on glaucoma and blood pressure). Albr v Graefe’s Archiv fuer Ophthalmologie 74(2):183–209
Kuzin AA et al (2010) Ocular biometry and open-angle glaucoma: the Los Angeles Latino Eye Study. Ophthalmology 117(9):1713–1719
Lavanya R et al (2010) Hyperopic refractive error and shorter axial length are associated with age-related macular degeneration: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci 51(12):6247–6252
Lee KE, Klein BE, Klein R (1999) Changes in refractive error over a 5-year interval in the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 40(8):1645–1649
Lee AJ et al (2003) Does smoking affect intraocular pres-sure? Findings from the Blue Mountains Eye Study. J Glaucoma 12(3):209–212
Leibowitz HM et al (1980) The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, mac-ular degeneration, and visual acuity in a general popu-lation of 2631 adults, 1973–1975. Surv Ophthalmol 24(Suppl):335–610
Leighton DA, Phillips CI (1972) Systemic blood pressure in open-angle glaucoma, low tension glaucoma, and the normal eye. Br J Ophthalmol 56(6):447–453
Leske MC (2009) Ocular perfusion pressure and glau-coma: clinical trial and epidemiologic fi ndings. Curr Opin Ophthalmol 20(2):73–78
Leske MC, Sperduto RD (1983) The epidemiology of senile cataracts: a review. Am J Epidemiol 118(2):152–165
Leske MC et al (2004) Nine-year incidence of lens opaci-ties in the Barbados Eye Studies. Ophthalmology 111(3):483–490
Leske MC et al (2006) Nine-year incidence of age-related macular degeneration in the Barbados Eye Studies. Ophthalmology 113(1):29–35
Leske MC et al (2007a) Predictors of long-term progres-sion in the early manifest glaucoma trial. Ophthalmology 114(11):1965–1972
Leske MC et al (2007b) Nine-year incidence of open-angle glaucoma in the Barbados Eye Studies. Ophthalmology 114(6):1058–1064
Leske MC et al (2008) Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology 115(1):85–93
Liew G et al (2006) Retinal vessel signs and 10-year inci-dent age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology 113(9):1481–1487
Liew G et al (2008) CKD increases the risk of age-related macular degeneration. J Am Soc Nephrol 19(4):806–811
Liew G, Mitchell P, Wong TY, Rochtchina E, Wang JJ (2013) The association of aspirin use with age-related macular degeneration. JAMA Intern Med 173(4):258–264
Lim LS et al (2009) Relation of age-related cataract with obesity and obesity genes in an Asian population. Am J Epidemiol 169(10):1267–1274
Lindblad BE et al (2005) Intensity of smoking and smok-ing cessation in relation to risk of cataract extraction: a prospective study of women. Am J Epidemiol 162(1):73–79
Ma L et al (2012) Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis. Br J Nutr 107(3):350–359
Mabuchi F et al (2010) Estrogen receptor beta gene poly-morphism and intraocular pressure elevation in female patients with primary open-angle glaucoma. Am J Ophthalmol 149(5):826–830
Maltzman BA, Mulvihill MN, Greenbaum A (1979) Senile macular degeneration and risk factors: a case–control study. Ann Ophthalmol 11(8):1197–1201
Marcus MW et al (2011) Myopia as a risk factor for open-angle glaucoma: a systematic review and meta-analy-sis. Ophthalmology 118(10):1989–1994
McCarty CA et al (2001) Risk factors for age-related mac-ulopathy: the Visual Impairment Project. Arch Ophthalmol 119(10):1455–1462
McCarty CA et al (2008) Novel measures of cardiovascu-lar health and its association with prevalence and pro-gression of age-related macular degeneration: the CHARM Study. BMC Ophthalmol 8:25
Mitchell P et al (1999) The relationship between glau-coma and myopia: the Blue Mountains Eye Study. Ophthalmology 106(10):2010–2015
Mitchell P et al (2002a) Bias in self-reported family his-tory and relationship to glaucoma: the Blue Mountains Eye Study. Ophthalmic Epidemiol 9(5):333–345
Mitchell P et al (2002b) Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 120(10):1357–1363
Mitchell P et al (2004) Open-angle glaucoma and sys-temic hypertension: the Blue Mountains Eye Study. J Glaucoma 13(4):319–326
Morris DS et al (2007) Corneal thickness at high altitude. Cornea 26(3):308–311
Mukesh BN et al (2002) Five-year incidence of open-angle glaucoma: the visual impairment project. Ophthalmology 109(6):1047–1051
Munoz B et al (2005) Prevalence of age-related macular degeneration in a population-based sample of Hispanic people in Arizona: Proyecto VER. Arch Ophthalmol 123(11):1575–1580
Nirmalan PK et al (2004) Female reproductive factors and eye disease in a rural South Indian population: the Aravind Comprehensive Eye Survey. Invest Ophthalmol Vis Sci 45(12):4273–4276
Nitsch D et al (2009) Associations between chronic kid-ney disease and age-related macular degeneration. Ophthalmic Epidemiol 16(3):181–186
Packer H et al (1959) Study of the frequency and distribu-tion of glaucoma. J Am Med Assoc 171:1090–1093
Paetkau ME et al (1978) Senile disciform macular degen-eration and smoking. Can J Ophthalmol 13(2):67–71
Patel JI (2007) Is cataract surgery a risk factor for progres-sion of macular degeneration? Curr Opin Ophthalmol 18(1):9–12
Peeters A et al (2008) Changes in abdominal obesity and age-related macular degeneration: the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 126(11):1554–1560
Perera SA et al (2010) Refractive error, axial dimensions, and primary open-angle glaucoma: the Singapore Malay Eye Study. Arch Ophthalmol 128(7):900–905
Perkins ES (1967) Tonometry. Proc R Soc Med 60(1):63–65
Piermarocchi S et al (2011) The prevalence of age-related macular degeneration in Italy (PAMDI) study: report 1. Ophthalmic Epidemiol 18(3):129–136
Quigley HA et al (2001) The prevalence of glaucoma in a population-based study of Hispanic subjects: Proyecto VER. Arch Ophthalmol 119(12):1819–1826
Rahman MM et al (2004) The prevalence of glaucoma in Bangladesh: a population based survey in Dhaka divi-sion. Br J Ophthalmol 88(12):1493–1497
Ramdas WD et al (2011a) Lifestyle and risk of developing open-angle glaucoma: the Rotterdam study. Arch Ophthalmol 129(6):767–772
Ramdas WD et al (2011b) Ocular perfusion pressure and the incidence of glaucoma: real effect or artifact? The Rotterdam Study. Invest Ophthalmol Vis Sci 52(9):6875–6881
Ramrattan RS et al (2001) Prevalence and causes of visual fi eld loss in the elderly and associations with impair-ment in daily functioning: the Rotterdam Study. Arch Ophthalmol 119(12):1788–1794
Rasker MT et al (1997) Deterioration of visual fi elds in patients with glaucoma with and without optic disc hemorrhages. Arch Ophthalmol 115(10):1257–1262
Ravindran RD et al (2011a) Inverse association of vitamin C with cataract in older people in India. Ophthalmology 118(10):1958–1965
Ravindran RD, Vashist P, Gupta SK, Young I, Maraini G et al (2011b) Prevalence and risk factors for vitamin C de fi ciency in north and south India: a two centre popu-lation based study in people aged 60 years and over. PLoS One 6(12):e28588
Ritter LL et al (1993) Alcohol use and lens opacities in the Beaver Dam Eye Study. Arch Ophthalmol 111(1):113–117
Rotchford AP et al (2003) Temba glaucoma study: a pop-ulation-based cross-sectional survey in urban South Africa. Ophthalmology 110(2):376–382
Rothman KJ, Greenland S (1998) Modern epidemiology, 2nd edn. Lippincott-Raven, Philadelphia
Rudnicka AR et al (2012) Age and gender variations in age-related macular degeneration prevalence in popu-lations of European ancestry: a meta-analysis. Ophthalmology 119(3):571–580
San fi lippo PG et al (2010) The heritability of ocular traits. Surv Ophthalmol 55(6):561–583
Sapkota YD et al (2010) The prevalence of blindness and cataract surgery in Rautahat District, Nepal. Ophthalmic Epidemiol 17(2):82–89
Sasaki K, Kojima M (1994) Population based cataract epi-demiological surveys utilising a photo documentation system. Doc Ophthalmol 88(3–4):277–283
Seddon JM et al (1994) Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degenera-tion. Eye Disease Case–control Study Group. JAMA 272(18):1413–1420
Seddon JM, George S, Rosner B (2006) Cigarette smok-ing, fi sh consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol 124(7):995–1001
Shiels A, Bennett TM, Hejtmancik JF (2010) Cat-Map: putting cataract on the map. Mol Vis 16:2007–2015
Shimmyo M et al (2003) Intraocular pressure, Goldmann applanation tension, corneal thickness, and corneal cur-vature in Caucasians, Asians, Hispanics, and African Americans. Am J Ophthalmol 136(4):603–613
54 P.T.V.M. de Jong
Sia DI et al (2010) Prevalence of and risk factors for pri-mary open-angle glaucoma in central Sri Lanka: the Kandy eye study. Ophthalmic Epidemiol 17(4):211–216
Skenduli-Bala E et al (2005) Causes of incident visual fi eld loss in a general elderly population: the Rotterdam study. Arch Ophthalmol 123(2):233–238
Smith BT, Belani S, Ho AC (2005) Light energy, cataract surgery, and progression of age-related macular degen-eration. Curr Opin Ophthalmol 16(3):166–169
Sommer A et al (1991) Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 109(8):1090–1095
Song W et al (2011) Prevalence of glaucoma in a rural northern china adult population: a population-based survey in Kailu County, Inner Mongolia. Ophthalmology 118(10):1982–1988
Spanish Eyes Epidemiological (SEE) Study Group (SEESG) (2011) Prevalence of age-related macular degeneration in Spain. Br J Ophthalmol 95:931–936
Sparrow JM et al (1986) The oxford clinical cataract classi fi cation and grading system. Int Ophthalmol 9(4):207–225
Sperduto RD et al (1993) The Linxian cataract studies. Two nutrition intervention trials. Arch Ophthalmol 111(9):1246–1253
Straub W (1969) Altersbedingte Maculadegeneration (age-related macular degeneration). Deutsche Mediz Wochenschr 26:1385–1386
Sun J, Zhou X, Kang Y, Yan L et al (2012) Prevalence and risk factors for primary open-angle glaucoma in a rural northeast China population: a population-based survey in Bin County, Harbin. Eye 26:283–291
Sunness JS et al (1985) Peripheral retinal function in age-related macular degeneration. Arch Ophthalmol 103(6):811–816
Tamakoshi A et al (1997) Smoking and neovascular form of age related macular degeneration in late middle aged males: fi ndings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 81(10):901–904
Tan JS et al (2007) Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol 143(4):685–687
Tan JS et al (2008a) Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology 115(2):334–341
Tan JS et al (2008b) Smoking and the long-term incidence of cataract: the Blue Mountains Eye Study. Ophthalmic Epidemiol 15(3):155–161
Tan JS et al (2009) Dietary fatty acids and the 10-year inci-dence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol 127(5):656–665
Tarkkanen A, Reunanen A, Kivela T (2008) Frequency of systemic vascular diseases in patients with primary open-angle glaucoma and exfoliation glaucoma. Acta Ophthalmol 86(6):598–602
Taylor HR et al (1992) The long-term effects of visible light on the eye. Arch Ophthalmol 110(1):99–104
The Eye Disease Case-Control Study Group (EDCCSG) (1992) Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol 110(12):1701–1708
The Italian-American Cataract Study Group (1991) Risk factors for age-related cortical, nuclear, and posterior subcapsular cataracts. Am J Epidemiol 133:541–553
Tielsch JM et al (1991) Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 266(3):369–374
Tielsch JM et al (1995) Diabetes, intraocular pressure, and primary open-angle glaucoma in the Baltimore Eye Survey. Ophthalmology 102(1):48–53
Tomany SC et al (2004) Risk factors for incident age-related macular degeneration: pooled fi ndings from 3 continents. Ophthalmology 111(7):1280–1287
van der Schaft TL et al (1994) Increased prevalence of disciform macular degeneration after cataract extrac-tion with implantation of an intraocular lens. Br J Ophthalmol 78(6):441–445
van Leeuwen R, Vingerling JR, de Jong PT (2001) Risk of macular degeneration with statin use should be inter-preted with caution. BMJ 323(7324):1308
van Leeuwen R et al (2003a) Blood pressure, atheroscle-rosis, and the incidence of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 44(9):3771–3777
van Leeuwen R et al (2003b) The risk and natural course of age-related maculopathy: follow-up at 6 1/2 years in the Rotterdam study. Arch Ophthalmol 121(4):519–526
van Leeuwen R et al (2005) Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 294(24):3101–3107
Vandenbroucke JP et al (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med 4(10):e297
VandenLangenberg GM et al (1998) Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol 148(2):204–214
Vashist P et al (2011) Prevalence of cataract in an older population in India: the India study of age-related eye disease. Ophthalmology 118(2):272–278
Vijaya L et al (2008) Prevalence of primary open-angle glaucoma in an urban south Indian population and comparison with a rural population. The Chennai Glaucoma Study. Ophthalmology 115(4):648–654
Vinding T et al (1992) Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmol (Copenh) 70(1):66–72
Vingerling JR et al (1995) Macular degeneration and early menopause: a case–control study. BMJ 310(6994):1570–1571
Wang JJ, Mitchell P, Smith W (1998) Refractive error and age-related maculopathy: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci 39(11):2167–2171
Wang JJ et al (2004) Refractive status and the 5-year inci-dence of age-related maculopathy: the Blue Mountains Eye Study. Clin Experiment Ophthalmol 32(3):255–258
Wang S, Wang JJ, Wong TY (2008) Alcohol and eye dis-eases. Surv Ophthalmol 53(5):512–525
Wang JJ et al (2009) Combined effects of complement factor H genotypes, fi sh consumption, and in fl ammatory mark-ers on long-term risk for age-related macular degenera-tion in a cohort. Am J Epidemiol 169(5):633–641
Wang X et al (2010a) Using the Utah Population Database to assess familial risk of primary open angle glaucoma. Vision Res 50(23):2391–2395
Wang YX et al (2010b) Prevalence of glaucoma in North China: the Beijing Eye Study. Am J Ophthalmol 150(6):917–924
Wang D et al (2011) Intraocular pressure, central corneal thickness, and glaucoma in Chinese adults: the Liwan eye study. Am J Ophthalmol 152(3):454–462
Waudby CJ et al (2011) Cataract research using electronic health records. BMC Ophthalmol 11:32
Weiner DE et al (2011) Kidney function, albuminuria and age-related macular degeneration in NHANES III. Nephrol Dial Transplant 26(10):3159–3165
West SK, Taylor HR (1986) The detection and grading of cataract: an epidemiologic perspective. Surv Ophthalmol 31(3):175–184
West SK, Valmadrid CT (1995) Epidemiology of risk factors for age-related cataract. Surv Ophthalmol 39(4):323–334
West S et al (1989a) Cigarette smoking and risk of nuclear cataracts. Arch Ophthalmol 107(8):1166–1169
West SK et al (1989b) Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 107(6):875–879
West SK et al (1998) Sunlight exposure and risk of lens opacities in a population-based study: the Salisbury Eye Evaluation project. JAMA 280(8):714–718
Wieberdink RG et al (2011) Age-related macular degen-eration and the risk of stroke: the Rotterdam study. Stroke 42(8):2138–2142
Wolfs RC et al (1997) Distribution of central corneal thickness and its association with intraocular pressure: the Rotterdam Study. Am J Ophthalmol 123(6):767–772
Wolfs RC et al (1998) Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol 116(12):1640–1645
Wolfs RC et al (2000) Changing views on open-angle glaucoma: de fi nitions and prevalences – The Rotterdam Study. Invest Ophthalmol Vis Sci 41(11):3309–3321
Wong TY et al (2002) Refractive errors and 10-year inci-dence of age-related maculopathy. Invest Ophthalmol Vis Sci 43(9):2869–2873
Wu SY et al (2005) Nine-year refractive changes in the Barbados Eye Studies. Invest Ophthalmol Vis Sci 46(11):4032–4039
Wu R et al (2010) Smoking, socioeconomic factors, and age-related cataract: The Singapore Malay Eye study. Arch Ophthalmol 128(8):1029–1035
Xu L, You QS, Jonas JB (2009) Prevalence of alcohol consumption and risk of ocular diseases in a general population: the Beijing Eye Study. Ophthalmology 116(10):1872–1879
Xu L, Wang YX, Jonas JB (2010) Level of education asso-ciated with ophthalmic diseases. The Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 248(1):49–57
Yanagi M et al (2011) Vascular risk factors in glaucoma: a review. Clin Experiment Ophthalmol 39(3):252–258
Yang K et al (2011) Prevalence of age-related macular degeneration in a rural Chinese population: the Handan Eye Study. Ophthalmology 118(7):1395–1401
Yasuda M et al (2009) Nine-year incidence and risk fac-tors for age-related macular degeneration in a de fi ned Japanese population the Hisayama study. Ophthalmology 116(11):2135–2140
Yip JL et al (2007) Socioeconomic status, systolic blood pressure and intraocular pressure: the Tanjong Pagar Study. Br J Ophthalmol 91(1):56–61
Younan C et al (2003) Cardiovascular disease, vascular risk factors and the incidence of cataract and cataract surgery: the Blue Mountains Eye Study. Ophthalmic Epidemiol 10(4):227–240
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